Addiction is a state characterized by compulsive engagement in rewarding stimuli, despite adverse consequences.[7] It can be thought of as a disease or biological process leading to such behaviors.[1][8] The two properties that characterize all addictive stimuli are that they are (positively) reinforcing (i.e., they increase the likelihood that a person will seek repeated exposure to them) and intrinsically rewarding (i.e., they activate the brain's "reward pathways", and are therefore perceived as being something positive or desirable).[1][3][6]ΔFosB, a gene transcription factor, is now known to be a critical component and common factor in the development of virtually all forms of behavioral and drug addictions.[9][10][11]

Addiction exacts a high toll on individuals and society as a whole through the direct adverse effects of drugs and associated healthcare costs, the functional consequences of altered neuroplasticity in the brain, and the loss of productivity.[12] Classic hallmarks of addiction include impaired control over substances or behavior, preoccupation with substance or behavior, continued use despite consequences, and denial.[13] Habits and patterns associated with addiction are typically characterized by immediate gratification (short-term reward), coupled with delayed deleterious effects (long-term costs).[14]

Potential addictions can include, but are not limited to, exercise addiction, food addiction, drug addiction, computer addiction, sex addiction and gambling addiction. Currently, only substance addictions and gambling addiction are recognized by the DSM-5, which uses physical dependence and the associated withdrawal syndrome to identify an addictive state. Physical dependence occurs when the body has adjusted by incorporating the substance into its "normal" functioning – i.e., attains homeostasis – and therefore physical withdrawal symptoms occur upon cessation of use.[15] Tolerance is the process by which the body continually adapts to the substance and requires increasingly larger amounts to achieve the original effects. Withdrawal refers to physical and psychological symptoms experienced when reducing or discontinuing a substance that the body has become dependent on. Symptoms of withdrawal generally include but are not limited to anxiety, irritability, intense cravings for the substance, nausea, hallucinations, headaches, cold sweats, and tremors.

It has long been established that genetic factors along with social and psychological factors are contributors to addiction. A common theory along these lines is the self-medication hypotheses. Epidemiological studies estimate that genetic factors account for 40–60% of the risk factors for alcoholism. Similar rates of heritability for other types of drug addiction have been indicated by other studies.[16] Knestler hypothesized in 1964 that a gene or group of genes might contribute to predisposition to addiction in several ways. For example, altered levels of a normal protein due to environmental factors could then change the structure or functioning of specific brain neurons during development. These altered brain neurons could change the susceptibility of an individual to an initial drug use experience. In support of this hypothesis, animal studies have shown that environmental factors such as stress can affect an animal's genotype.[16]

Overall, the data implicating specific genes in the development of drug addiction is mixed for most genes. One reason for this may be that the case is due to a focus of current research on common variants. Many addiction studies focus on common variants with an allele frequency of greater than 5% in the general population, however when associated with disease, these only confer a small amount of additional risk with an odds ratio of 1.1–1.3. On the other hand, the rare variant hypothesis states that genes with low frequencies in the population (<1%) confer much greater additional risk in the development of disease.[17]

Genome-wide association studies (GWAS) are a recently developed research method which are used to examine genetic associations with dependence, addiction, and drug use. These studies employ an unbiased approach to finding genetic associations with specific phenotypes and give equal weight to all regions of DNA, including those with no ostensible relationship to drug metabolism or response. These studies rarely identify genes from proteins previously described via animal knockout models and candidate gene analysis. Instead, large percentages of genes involved in processes such as cell adhesion are commonly identified. This is not to say that previous findings, or the GWAS findings, are erroneous. The important effects of endophenotypes are typically not capable of being captured by these methods. Furthermore, genes identified in GWAS for drug addiction may be involved either in adjusting brain behavior prior to drug experiences, subsequent to them, or both. [18]

This diagram depicts the signaling events in the brain's reward center that are induced by chronic high-dose exposure to psychostimulants that increase the concentration of synaptic dopamine, like amphetamine, methylphenidate, and phenethylamine. Following presynaptic dopamine and glutamateco-release by such psychostimulants,[19][20]postsynaptic receptors for these neurotransmitters trigger internal signaling events through a cAMP pathway and calcium-dependent pathway that ultimately result in increased CREB phosphorylation.[21][22] Phosphorylated CREB increases levels of ΔFosB, which in turn represses the c-fos gene with the help of corepressors;[22] c-fos repression acts as a molecular switch that enables the accumulation of ΔFosB in the neuron.[23] A highly stable (phosphorylated) form of ΔFosB, one that persists in neurons for one or two months, slowly accumulates following repeated exposure to stimulants through this process.[24][25] ΔFosB functions as "one of the master control proteins" that produces addiction-related structural changes in the brain, and upon sufficient accumulation, with the help of its downstream targets (e.g., nuclear factor kappa B), it induces an addictive state.[24][25]

ΔFosB also plays an important role in regulating behavioral responses to natural (non-drug) rewards, such as palatable food, sex, and exercise.[9][10] Natural rewards, like drugs of abuse, induce gene expression of ΔFosB in the nucleus accumbens, and chronic acquisition of these rewards can result in a similar pathological addictive state through ΔFosB overexpression.[9][10][11] Consequently, ΔFosB is the key transcription factor involved in addictions to natural rewards (i.e., behavioral addictions) as well;[9][10][11] in particular, ΔFosB in the nucleus accumbens is critical for the reinforcing effects of sexual reward.[10] Research on the interaction between natural and drug rewards suggests that dopaminergic psychostimulants (e.g., amphetamine) and sexual behavior act on similar biomolecular mechanisms to induce ΔFosB in the nucleus accumbens and possess bidirectional cross-sensitization effects that are mediated through ΔFosB.[11][29] This phenomenon is notable since, in humans, a dopamine dysregulation syndrome, characterized by drug-induced compulsive engagement in natural rewards (specifically, sexual activity, shopping, and gambling), has also been observed in some individuals taking dopaminergic medications.[11]

ΔFosB inhibitors (drugs or treatments that oppose its action) may be an effective treatment for addiction and addictive disorders.[30]

The release of dopamine in the nucleus accumbens plays a role in the reinforcing qualities of many forms of stimuli, including naturally reinforcing stimuli like palatable food and sex.[31][32] Altered dopamine neurotransmission is frequently observed following the development of an addictive state.[11] In humans and lab animals that have developed an addiction, alterations in dopamine or opiate neurotransmission in the nucleus accumbens and other parts of the striatum are evident.[11] Studies have found that use of certain drugs (e.g., nicotine) affect cholinergic neurons that innervate the reward system, in turn affecting dopamine signaling in this region.[33]

Understanding the pathways in which drugs act and how drugs can alter those pathways is key when examining the biological basis of drug addiction. The reward pathway, known as the mesolimbic pathway, or its extension, the mesocorticolimbic pathway, is characterized by the interaction of several areas of the brain.

The projections from the ventral tegmental area (VTA) are a network of dopaminergicneurons with co-localized postsynaptic glutamate receptors (AMPAR and NMDAR). These cells respond when stimuli indicative of a reward are present. The VTA supports learning and sensitization development and releases DA into the forebrain.[35] These neurons also project and release DA into the nucleus accumbens,[36] through the mesolimbic pathway. Virtually all drugs causing drug addiction increase the dopamine release in the mesolimbic pathway,[37] in addition to their specific effects.

The nucleus accumbens (NAcc) is one output of the VTA projections. The nucleus accumbens itself consists mainly of GABAergicmedium spiny neurons (MSNs).[38] The NAcc is associated with acquiring and eliciting conditioned behaviors, and is involved in the increased sensitivity to drugs as addiction progresses.[35] Overexpression of ΔFosB in the nucleus accumbens is a necessary common factor in essentially all known forms of addiction;[1] ΔFosB is a strong positive modulator of positively reinforced behaviors.[1]

The hippocampus is involved in drug addiction, because of its role in learning and memory. Much of this evidence stems from investigations showing that manipulating cells in the hippocampus alters dopamine levels in NAcc and firing rates of VTA dopaminergic cells.[36]

Dopamine is the primary neurotransmitter of the reward system in the brain. It plays a role in regulating movement, emotion, cognition, motivation, and feelings of pleasure.[40] Natural rewards, like eating, as well as recreational drug use cause a release of DA, and are associated with the reinforcing nature of these stimuli.[40][41] Nearly all addictive drugs, directly or indirectly, act upon the brain’s reward system by heightening dopaminergic activity.[42]

Excessive intake of many types of addictive drugs results in repeated release of high amounts of DA, which in turn affects the reward pathway directly through heightened dopamine receptor activation. Prolonged and abnormally high levels of DA in the synaptic cleft can induce receptor downregulation in along the neural pathway. Downregulation of mesolimbic DA receptors can result in a decrease in the sensitivity to natural reinforcers.[40]

Drug seeking behavior is induced by glutamatergic projections from the prefrontal cortex to the NAc. This idea is supported with data from experiments showing that drug seeking behavior can be prevented following the inhibition of AMPA glutamate receptors and glutamate release in the NAc.[34]

Sensitization, or reverse tolerance, is the increase in sensitivity to a drug after repeated use. The protein ΔFosB (Delta-FosB) is known to be involved in drug and behavioral sensitization. The ΔFosB transcription factor activates genes that, counter to the effects of CREB, actually increase the user's sensitivity to the effects of the substance. A stable form of ΔFosB slowly builds up with each exposure to the drug and remains activated for 1–2 months after the last exposure—long after the effects of CREB have faded. The hypersensitivity that it causes is thought to be responsible for the intense cravings associated with drug addiction, and is often extended to even the peripheral cues of drug use, such as related behaviors or the sight of drug paraphernalia. There is also very significant evidence that ΔFosB causes behavioral plasticity and structural changes within the nucleus accumbens, which helps to perpetuate cravings and relapses in addicts.[43][44][45][46][47][48][49][50][51][52][53][54][55]

The regulator of G-protein signaling 9-2 (RGS9-2) is also thought to be involved in sensitization. Regulator of G-protein Signaling 9-2 (RGS9-2) has recently been the subject of several animal knockout studies. Animals lacking RGS9-2 appear to have increased sensitivity to dopamine receptor agonists such as cocaine and amphetamines; over-expression of RGS9-2 causes a lack of responsiveness to these same agonists. RGS9-2 is believed to catalyze inactivation of the G-protein coupled D2 receptor by enhancing the rate of GTP hydrolysis of the G alpha subunit which transmits signals into the interior of the cell.[56][57][58][59][60][61][62][63]

In addition to the traditional behavioral self-help groups and programs available for rehabilitation, there is a varied array of preventive and therapeutic approaches to combating addiction. For example, a common treatment option for opiate addiction is methadone maintenance. This process consists of administering the drug, a potent opiate with some potential for abuse, as a drink in a supervised clinical setting. In this way, the brain opiate levels increase slowly without producing the high but remain in the system long enough to deter addicts from injecting heroin.

Another form of drug therapy involves buprenorphine, a drug which seems to be even more promising than methadone.[64] A partial agonist for certain opiate receptors, this treatment blocks the effects of opiates but produces only mild reactions itself. Moreover, this method of detoxification has little value in the drug market.

New research indicates that it may even be possible to develop antibodies which combat a particular drug's effect on the brain, rendering the pleasurable effects null. Recently, vaccines have been developed against cocaine, heroin, methamphetamine, and nicotine. These advances are already being tested in human clinical trials and show serious promise as a preventive and recovery measure for addicts or those prone to addiction.[65][66]

Furthermore, another method of treatment for addiction that is being studied is deep brain stimulation. A serious procedure, DBS targets several brain regions including the nucleus accumbens, subthalamic nucleus, dorsal striatum, and medial prefrontal cortex among others.[67] Other studies have concurred and demonstrated that stimulation of the nucleus accumbens, an area that is apparently one of the most promising regions, allowed a seventy-year-old man to stop smoking without issue and attain a normal weight.[68]

Other forms of treatment include replacement drugs such as suboxone or subutex (both containing the active ingredient buprenorphine) and methadone; these are used as substitutes for illicit opiate drugs.[69][70] Although these drugs perpetuate physical dependence, the goal of opiate maintenance is to provide a clinically supervised, stable dose of a particular opioid in order to provide a measure of control to both pain and cravings. This provides a chance for the addict to function normally and to reduce the negative consequences associated with obtaining sufficient quantities of controlled substances illicitly, by both reducing opioid cravings and withdrawal symptomology. Once a prescribed dosage is stabilized, treatment enters maintenance or tapering phases. In the United States, opiate replacement therapy is tightly regulated in methadone clinics and under the DATA 2000 legislation. In some countries, other opioid derivatives such as levomethadyl acetate,[71]dihydrocodeine,[72]dihydroetorphine[73] and even heroin[74][75] are used as substitute drugs for illegal street opiates, with different drugs being used depending on the needs of the individual patient. Baclofen has been shown successful in attenuating cravings for most drugs of abuse – stimulants, ethanol, and opioids – and also attenuates the actual withdrawal syndrome of ethanol. Many patients have stated they "became indifferent to alcohol" or "indifferent to cocaine" overnight after starting baclofen therapy.[76] It is possible that one of the best, albeit relatively unexplored, treatment modalities for opioid addiction – notoriously the most difficult addiction to treat (and to recover from), having relapse rates of around 23% at four weeks and 57% at twelve months if not on maintenance therapy with a mu-opioid agonist[76] – would be to combine an opioid maintenance agent, such as methadone or buprenorphine, to block withdrawal symptomology, with baclofen, to attenuate cravings and the desire to use, in people who find that they are still using or still craving drugs while on methadone or buprenorphine maintenance.

Substitute drugs for other forms of drug addiction have historically been less successful than opioid substitute treatment, but some limited success has been seen with drugs such as dextroamphetamine to treat stimulant addiction,[77][78] and clomethiazole to treat alcohol addiction.[79]Bromocriptine and desipramine have been reported to be effective for treatment of cocaine but not amphetamine addiction.[80]

Other pharmacological treatments for alcohol addiction include drugs like naltrexone, disulfiram, acamprosate and topiramate,[81][82] but rather than substituting for alcohol, these drugs are intended to reduce the desire to drink, either by directly reducing cravings as with acamprosate and topiramate, or by producing unpleasant effects when alcohol is consumed, as with disulfiram. These drugs can be effective if treatment is maintained, but compliance can be an issue as alcoholic patients often forget to take their medication, or discontinue use because of excessive side effects.[83][84] Additional drugs acting on glutamate neurotransmission such as modafinil, lamotrigine, gabapentin and memantine have also been proposed for use in treating addiction to alcohol and other drugs.[85]

Opioid antagonists such as naltrexone and nalmefene have also been used successfully in the treatment of alcohol addiction,[86][87] which is often particularly challenging to treat. Some have also attempted to use these drugs for maintenance treatment of former opiate addicts with little success. They cannot be started until the patient has been abstinent for an extended period – unlikely with opioid addicts who are not on maintenance with a full or partial mu-opioid agonist – or they will trigger acute opioid withdrawal symptoms. No study has found them to be efficacious treatments in preventing relapse. They do nothing to block craving, and block endorphin and enkephalin, two natural neurotransmitters that regulate one's sense of well-being. An addict must discontinue the drug for just eighteen hours in order to use again.[88]

Another area in which drug treatment has been widely used is in the treatment of nicotine addiction. Various drugs have been used for this purpose such as bupropion, mecamylamine and the more recently developed varenicline. The cannaboinoid antagonist rimonabant has also been trialled for treatment of nicotine addiction but has not been widely adopted for this purpose.[92][93][94]

Ibogaine is a hallucinogen (psychotomimetic) that some claim interrupts addiction and reduces or eliminates withdrawal syndromes, specifically in regards to opioids.[95] Its mechanism of action is unknown, but likely linked to nAchR α3ß4 antagonism. In one animal trial, it was shown to slightly reduce self-administration of cocaine.[96] Another uncontrolled trial showed it reduced tremor by a mild to moderate degree during morphine withdrawal in rats.[97] These finding can not be extrapolated to human beings with any certainty. Research is complicated by the fact that ibogaine is illegal in many developed countries, and a Schedule I substance in the US, and as a result no controlled human trials have ever been performed. A semi-synthetic analogue of ibogaine, 18-methoxycoronaridine was developed, in an attempt to reduce the toxic (ibogaine is significantly cardiotoxic, and several deaths have been reported from its use; because of its illegal, underground nature, it is impossible to know how toxic the drug is) and psychotomimetic effects of the drug.

Research has consistently shown strong associations between affective disorders and substance use disorders. Specifically, people with mood disorders are at increased risk of substance use disorders.[98] Affect and addiction can be related in a variety of ways as they play a crucial role in influencing motivated behaviours. For instance, affect facilitates action, directs attention, prepares the individual for a physical response, and guides behaviour to meet particular needs.[99] Moreover, affect is implicated in a range of concepts relevant to addiction: negative reinforcement and positive reinforcement, behaviour motivation, regulation of cognition and mood, and reasoning and decision making.[100][101] Emotion-motivated reasoning has been shown to influence addictive behaviours via selecting outcomes that minimize negative affective states while maximizing positive affective states.[102]

The relationship between negative affect and substance use disorders has been the most widely studied model of addiction. It proposes that individuals who experience the greatest levels of negative affect are at the greatest risk of using substances or behaviours as a coping (psychology) mechanism.[103][104] Here, substances and behaviours are used to improve mood and distract from unpleasant feelings. Once physical dependence has been established, substance abuse is primarily motivated by a desire to avoid negative affective states associated with withdrawal. Individuals high in affective mood disorders (anxiety) most commonly report high levels of negative affect associated with cravings.[105][106][107] The relationship between negative affect and addiction is not unidirectional. That is, while positive affect increases the likelihood of initiation of substance use, the negative affective states produced by withdrawal are the most commonly reported factors for continued use.[98]

Key to this concept is the Hedonic Hypothesis, which states that individuals initiate use of the substance or behaviour for their pleasurable effects, but then take it compulsively to avoid withdrawal symptoms, resulting in dependence.[108] Based on this hypothesis, some researchers believe that individuals engaging in risky use of substances or behaviours may be over-responsing to negative stimuli, which leads to addiction.

Negative affect has also been a powerful predictor in terms of vulnerability to addiction in adolescents. High-risk adolescents have been found to be highly reactive to negative stimuli, which increases their motivation to engage in substance use following a negative emotion-arousing situation.[109] Moreover, it has been established that adolescents high in negative affect are at increased risk for moving from recreational use to problematic use despite a family history of addiction.[109]

Furthermore, the trait negative urgency, the propensity to engage in risky behaviour in response to distress, is highly predictive of certain aspects of substance abuse in adolescents.[110] Early individual differences in emotional differences in reactivity and regulation underlie the later emergence of the trait 'negative urgency'.[111]

Unlike negative affect, positive affect is related to addiction in both high and low forms. For example, individuals high in positive affect are more likely to engage in risky behaviour, such as drug use. Individuals with high positive affect in response to use are more likely to seek out substances for hedonic reasons. Conversely, low positive affect may prompt initial use due to lack of responsiveness to natural rewards.[98]

Extensive personality research has been done that links positive emotional states to individual differences in risky behaviour.[98] The trait positive urgency, defined as the tendency to engage in risky behaviour under conditions of extreme positive affect, is predictive of substance or behavioural problems that lead to addiction.[112] This trait represents an underlying dysregulation in response to extreme affective states and has a direct impact on behaviour. The trait 'positive urgency' has been shown to have a predictive relationship with increases in drinking quantity and alcohol-related problems in college, as well as drug use in college.[110][113] Furthermore, this trait provides important information on how positive affect can increase the likelihood of engaging in substance abuse.

Another important factor to consider is the individual differences in the experience of pleasurable effects brought on by the substance or behaviour. It is reasoned that certain individuals may be more sensitive to the pleasurable effects and thus experience them with greater intensity, resulting in addiction.[98] For example, over-responsiveness to substance affects has been found in cocaine addicts - an increased response to methylphenidate in the brain regions associated with emotional reactivity and mood.[114][115][116] Thus, strong emotional responses that addicted individuals show in response to substances or behaviours might be results of enhanced sensitivity to their effects.

Individuals differ in the way by which they metabolize substances, such as alcohol; these positive reinforcing effects are partly predetermined.[98] Individual reactivity to the effects of substances may affect motivation to use. For example, if a person experiences strong positive (and weak negative) effects from a substance, due to their biochemical profile, their expectations of the positive effects from the substance will be heightened, therefore increasing their desire for continued use, resulting in dependence.[98] According to this model, the experience of the positive mood enhances implicit attention to substance cues and implicit associations between reward and substance use.[117]

Interestingly, many addicts report symptoms of anhedonia (i.e., the inability to experience pleasure).[118] Results of chronic deviation of the brain's reward set point, which follow a prolonged intoxication, diminish responsiveness to natural positive stimuli. This may result in an over-responsiveness to substance-related cues, coupled with an impaired capacity to initiate behaviours in response to natural rewards.[119] Thus, low positive affect inhibits the individual's ability to replace drug-taking with other rewarding activities. It has also been proposed that during substance dependence the somatic states that guide decision-making are weakened in relation to natural rewards, while at the same time they enhance the emotional response to drug-related stimuli.[120]

Compulsive behaviours characterized by addiction are underpinned by two interacting systems: (a) impulsivity, and (b) reflection. Impulsivity is responsible for the rapid signalling of the affective importance of a stimuli. Reflection cognitively evaluates the signal before altering the behavioural response. Dysfunction in impulsivity exaggerates the emotional impact of the drug-related stimuli and attenuates the impact of natural reinforcement.[98] Dysregulation in reflection results in the inability to override impulsivity, thus resulting in addiction.[98] Under-responsiveness to naturally occurring positive stimuli is a crucial element that biases the individual towards the use of substances or behaviours and away from non-drug alternatives.

Temperamental effortful control is defined as the ability to suppress a dominant response in order to perform a subdominant response.[121] In other words, it is the degree of control the individual has over impulses and emotions, which includes the ability to focus or shift attention. Temperamental effortful control can influence addiction in a number of ways.

Low levels of effortful control can render the individual less able to distract themselves from unpleasant feelings or overcome strong affective impulses, resulting in maladaptive responses to distress - such as continued substance use.[98] Low effortful control may also interact with negative and positive affect, predisposing individuals to substance or behavioural use, and impair their ability to control use.[98]

A general inability to control affective states may impair the conditioning of behaviour associated with rewards and punishment, may increase susceptibility to biasing by substance-related cues, and could tax self-regulatory capacity.[98] Such conditions may render individuals unable to interrupt automatic drug-seeking behaviours. Abnormal levels of positive and negative affect can be increased by low effortful control.[122][123] For example, high positive affect may interact with low effortful control in increasing risk of addiction amongst vulnerable populations.

Gray's Reinforcement sensitivity theory (RST) consists of two motivational systems: the Behaviour Inhibition System (BIS) and the Behaviour Activation System (BAS).[124][125] The BIS is responsible for organizing behaviour in response to adverse stimuli. In other words, stimuli associated with punishment or the omission/termination of reward, are believed to underlie anxiety. The purpose of the BIS is to initiate behaviour inhibition, or interrupt ongoing behaviour, while the BAS is sensitive to stimuli that signal reward and/or relief from punishment (impusivity).[124][125] In accordance with the RST, an association was found between people with extreme scores in BIS/BAS and adjustment problems. BIS and BAS reactivity correspond with individual trait differences in positive affect and negative affect - The BAS is associated with trait impulsivity and positive affect, while the BIS is associated with trait negative affect.[126][127] For instance, it has been postulated that high BIS is related to anxiety, while high BAS is related to conduct disorders or impulsivity.[125][128]

According to this model substance abuse problems may arise under two different personality traits: low BIS and high BAS. Since the BAS promotes the individual to pursue actions that may result in reward, BAS sensitivity is involved in the initiation of addiction. Significant associations have been found between high BAS such as alcohol misuse in school girls, hazardous drinking in men, illicit drug abuse, and tobacco use. BAS sensitivity is a significant predictor of reactivity to substance cues, or cravings.[129][130][131][132][133][134][135][136] Conversely, BIS sensitivity is involved in avoiding negative situations or affect (such as withdrawal). Low BIS has been positively associated with continuing the addiction to relieve feelings of withdrawal, or for continued use to alleviate negative affect.

The model of impulsivity states that individuals high in impulsivity are at greater risk of addictive behaviours. The model proposes a two dimensional trait characteristic for the initiation and continuation of substance/behavioural abuse:

Rash Impulsiveness (RI) - reflecting individual differences in the ability to modify the addictive behaviour due to negative consequences.[137] Individuals high in RI are oblivious or insensitive to the negative consequences as a result of addictive behaviour when engagement is craved.

Both high RD and RI individuals are found to have difficulty in making decisions that have future consequences. Individuals high in RD experience greater reinforcement when initially engaging in the addictive behaviour, and experience stronger conditioned associations with continued use. Individuals high in RI experience greater difficulty resisting cravings even in the face of negative consequences.[137] Some moderators of RD and RI on the severity of addiction are stress and negative affect (such as feeling depressed).[138] That is, individuals high in RD/RI who also experience high levels of negative affect or stress, present more severe addictive behaviours. For example, if an individual is experiencing emotional distress, the distress experienced may lessen impulse control if they believe that engaging in addictive behaviour will decrease negative affect. According to this model, adolescents who are high in RI are at greater risk for developing addictions. Interestingly, low RI has been shown to moderate some of the risk of addiction due to family history.[139][140][141][142] High RI for individual without a family history of addiction has been related to poor decision-making.

Each personality dimension lies on a spectrum ranging from low to high. For example, individuals high in NS are impulsive, while individual's low in NS are reflective. Interactions between each of these three personality dimensions lead to different responses to novelty, punishment and rewards.[143]

This model was extended to alcohol use disorders proposing that individuals with alcohol use disorders have extreme temperaments (i.e. are very high or very low in NS, HA, and RD).[144] This model proposes that alcoholics can be classified in two groups based on the combinations of their three personality dimensions:[143]

Type I alcoholics have a late onset of alcohol-related problems, experience guilt and fear associated with consumption, lose control once drinking is initiated, engage in alcohol-related antisocial conduct, and rarely exhibit spontaneous alcohol-seeking behaviour.[145] Type I alcoholics are thought to be low in NS and high in HA and RD, exhibiting behaviors that are motionally dependent, rigid, perfectionistic, anxious, quiet, patient, and introverted.[145]

Type II alcoholics have an earlier onset of alcohol-related problems, less ability to abstain from alcohol, more frequent alcohol-related antisocial behaviour, less loss of control once drinking commenced, and less guilt or fear associated with drinking.[145] These individuals are high in NS, and low in HA and RD, which means they may be typically aggressive, impulsive, active, talkative, and impatient.[145]

^ abYoshida T (1997). Klee H, ed. Amphetamine Misuse: International Perspectives on Current Trends. Amsterdam, Netherlands: Harwood Academic Publishers. p. 5. ISBN9789057020810. Retrieved 1 December 2014. In summary, the essential component of [drug addiction] is a strong desire or a sense of compulsion (craving) to take the drug as manifested by drug-seeking behaviour which is difficult to control. Withdrawal syndrome and tolerance (a reduction in the sensitivity to a drug following its repeated administration) are both considered merely as consequences of drug exposure which, alone, are not sufficient evidence for a positive diagnosis of [drug addiction].
In pharmacology, when a drug is a reinforcer, it makes the desire for the drug stronger as the subject continues using the drug. Therefore repeated use of drugs having marked reinforcing efficacy can easily lead to a state of [drug addiction].

^ abcdefghijRobison AJ, Nestler EJ (November 2011). "Transcriptional and epigenetic mechanisms of addiction". Nat. Rev. Neurosci.12 (11): 623–637. doi:10.1038/nrn3111. PMC3272277. PMID21989194. ΔFosB has been linked directly to several addiction-related behaviors ... Importantly, genetic or viral overexpression of ΔJunD, a dominant negative mutant of JunD which antagonizes ΔFosB- and other AP-1-mediated transcriptional activity, in the NAc or OFC blocks these key effects of drug exposure14,22–24. This indicates that ΔFosB is both necessary and sufficient for many of the changes wrought in the brain by chronic drug exposure. ΔFosB is also induced in D1-type NAc MSNs by chronic consumption of several natural rewards, including sucrose, high fat food, sex, wheel running, where it promotes that consumption14,26–30. This implicates ΔFosB in the regulation of natural rewards under normal conditions and perhaps during pathological addictive-like states.

^ abcdeBlum K, Werner T, Carnes S, Carnes P, Bowirrat A, Giordano J, Oscar-Berman M, Gold M (2012). "Sex, drugs, and rock 'n' roll: hypothesizing common mesolimbic activation as a function of reward gene polymorphisms". J. Psychoactive Drugs44 (1): 38–55. doi:10.1080/02791072.2012.662112. PMC4040958. PMID22641964. It has been found that deltaFosB gene in the NAc is critical for reinforcing effects of sexual reward. Pitchers and colleagues (2010) reported that sexual experience was shown to cause DeltaFosB accumulation in several limbic brain regions including the NAc, medial pre-frontal cortex, VTA, caudate, and putamen, but not the medial preoptic nucleus. Next, the induction of c-Fos, a downstream (repressed) target of DeltaFosB, was measured in sexually experienced and naive animals. The number of mating-induced c-Fos-IR cells was significantly decreased in sexually experienced animals compared to sexually naive controls. Finally, DeltaFosB levels and its activity in the NAc were manipulated using viral-mediated gene transfer to study its potential role in mediating sexual experience and experience-induced facilitation of sexual performance. Animals with DeltaFosB overexpression displayed enhanced facilitation of sexual performance with sexual experience relative to controls. In contrast, the expression of DeltaJunD, a dominant-negative binding partner of DeltaFosB, attenuated sexual experience-induced facilitation of sexual performance, and stunted long-term maintenance of facilitation compared to DeltaFosB overexpressing group. Together, these findings support a critical role for DeltaFosB expression in the NAc in the reinforcing effects of sexual behavior and sexual experience-induced facilitation of sexual performance. ... both drug addiction and sexual addiction represent pathological forms of neuroplasticity along with the emergence of aberrant behaviors involving a cascade of neurochemical changes mainly in the brain's rewarding circuitry.

^ abcdefghijklmnopqrstuvOlsen CM (December 2011). "Natural rewards, neuroplasticity, and non-drug addictions". Neuropharmacology61 (7): 1109–1122. doi:10.1016/j.neuropharm.2011.03.010. PMC3139704. PMID21459101. Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from “normal” to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."Table 1"

^Morse RM, Flavin DK (August 1992). "The definition of alcoholism. The Joint Committee of the National Council on Alcoholism and Drug Dependence and the American Society of Addiction Medicine to Study the Definition and Criteria for the Diagnosis of Alcoholism". JAMA268 (8): 1012–4. doi:10.1001/jama.1992.03490080086030. PMID1501306.